The main aims, in brief, are to (1) test the efficacy of image-guided hypofractionated intensity modulated radiotherapy (IMRT) in a Phase III randomized trial of prostate cancer patients with intermediate-to-high risk prostate cancer, (2) establish the relationship of abnormal bcl-2 and bax expression to patient outcome after radiotherapy (RT) with and without androgen deprivation (AD), and (3) determine if antisense strategies based on reducing bcl-2 expression will improve prostate cancer response to AD, RT, and AD+RT using tumor models. Radiotherapy, given alone or in combination with AD, remains the mainstay of treatment for intermediate-to-high risk patients. The best methods for administering RT, integrating AD+RT, and further promoting cell killing via manipulation of the apoptotic pathway remain to be established. The primary hypotheses of the work proposed are that (1) freedom from biochemical and/or disease failure (FFF) may be significantly enhanced using IMRT to deliver higher biologic doses in a hypofractionated regimen, (2) the abnormal expression of the key apoptotic pathway proteins bcl-2 and bax adversely effect radiation response, and (3) bcl-2 and bax control prostate cancer response to AD, RT and AD+RT such that the modulation of these apoptotic pathway proteins via antisense bcl-2 (AS-bcl-2) and/or antisense cAMP-dependent protein kinase A type I (AS-PKA) will render prostate cancer cells more sensitive to these treatments. The clinical trial compares FFF and toxicity after 76 Gy in 38 fractions to 70.2 Gy in 26 fraction (biologically equivalent to 84.3 Gy assuming an alpha/beta of 1.5) in 300 patients. Bcl-2 and bax will be measured immunohistochemically in diagnostic tissue prospectively from this trial and retrospectively from two Radiation Therapy Oncology Group trials (86-10 and 92-02), and correlated with patient outcome. The effect of altering bcl-2 expression with AS-bcl-2 and AS-PKA on cell death in vitro and orthotopic tumor growth in vivo will be determined using wild type, bcl-2 overexpressing, and androgen deprivation resistant LNCaP cells.